Crenigacestat | LY3039478 | Notch/γ-secretase Inhibitor

Crenigacestat {[allProObj[0].p_purity_real_show]}

货号：A236352 同义名： LY3039478

Crenigacestat是一种新型的强效Notch抑制剂，IC50为0.41 nM。

Crenigacestat 化学结构
CAS号：1421438-81-4

Crenigacestat 3D分子结构
CAS号：1421438-81-4

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Crenigacestat 生物活性

描述

LY3039478 is a potent Notch-1 intracellular domain (N1ICD) cleavage inhibitor with IC50 value of 0.41nM in SAR assays^[1]. It inhibited N1ICD cleavage and expression of Notch-regulated genes in the tumor microenvironment, and also resulted in the induction of apoptosis in a Notch-dependent xenograft model^[2]. LY3039478 at concentration of 1μM and 10μM significantly inhibited the growth of Caki and 769-P, with decreased expression of Myc and Cyclin A1, two protein driven by Notch. G0/G1 cell cycle arrest could also be observed. Oral administration of LY3039478, 3 days per week, led a significant increase of survival and delayed tumor growth of immunodeficient NSG mice xenografted with 769-P CCRCC cells^[3].

Crenigacestat 细胞实验

Cell Line Cardiac Fibroblasts MM.1S cells OPM-2 cells KKU-M213 and KKU-M156 hetero-spheroids Human primary CAFs	Concentration	Treated Time	Description	References
Cardiac Fibroblasts	10 µM	18 hours	Inhibit Notch1 signaling pathway, counteract the protective effect of FSTL1 on cardiac fibroblasts	Front Cell Dev Biol. 2021 Dec 9;9:757068.
MM.1S cells	10 nM	72 hours	Crenigacestat alone and in combination with ATRA enhanced BCMA expression, with the combination showing the strongest effect.	Haematologica. 2023 Feb 1;108(2):568-580.
OPM-2 cells	10 nM	72 hours	Crenigacestat alone and in combination with ATRA enhanced BCMA expression, with the combination showing the strongest effect.	Haematologica. 2023 Feb 1;108(2):568-580.
KKU-M213 and KKU-M156 hetero-spheroids	5 µM	96 hours	Crenigacestat significantly reduced KKU-M213 and KKU-M156 hetero-spheroids viability compared to vehicle.	J Exp Clin Cancer Res. 2024 Oct 17;43(1):286.
Human primary CAFs	1, 5, 10 µM		Crenigacestat significantly inhibited the intracellular domain of Notch1 (NICD1) and downregulated the HES1 gene at both mRNA and protein levels, indicating that CAFs are also a target of Crenigacestat.	J Exp Clin Cancer Res. 2022 Nov 28;41(1):331.

Cell Line

Cardiac Fibroblasts MM.1S cells OPM-2 cells KKU-M213 and KKU-M156 hetero-spheroids Human primary CAFs

Concentration

Treated Time

Description

References

Cardiac Fibroblasts

10 µM

18 hours

Inhibit Notch1 signaling pathway, counteract the protective effect of FSTL1 on cardiac fibroblasts

Front Cell Dev Biol. 2021 Dec 9;9:757068.

MM.1S cells

10 nM

72 hours

Crenigacestat alone and in combination with ATRA enhanced BCMA expression, with the combination showing the strongest effect.

Haematologica. 2023 Feb 1;108(2):568-580.

OPM-2 cells

10 nM

72 hours

Crenigacestat alone and in combination with ATRA enhanced BCMA expression, with the combination showing the strongest effect.

Haematologica. 2023 Feb 1;108(2):568-580.

KKU-M213 and KKU-M156 hetero-spheroids

5 µM

96 hours

Crenigacestat significantly reduced KKU-M213 and KKU-M156 hetero-spheroids viability compared to vehicle.

J Exp Clin Cancer Res. 2024 Oct 17;43(1):286.

Human primary CAFs

1, 5, 10 µM

Crenigacestat significantly inhibited the intracellular domain of Notch1 (NICD1) and downregulated the HES1 gene at both mRNA and protein levels, indicating that CAFs are also a target of Crenigacestat.

J Exp Clin Cancer Res. 2022 Nov 28;41(1):331.

Crenigacestat 动物实验

Species NSG mice CD1 nude mice Mice CD-1 Nude mice CD-1 Nude mice	Animal Model MM.1S xenograft model Xenograft model PDX model and hydrodynamic model HuCCT1-xenograft model iCCA xenograft model	Administration	Dosage	Frequency	Description	References
NSG mice	MM.1S xenograft model	Intraperitoneal injection	1 mg/kg	Once daily for 12 days	Combination treatment with ATRA and crenigacestat significantly enhanced the anti-myeloma efficacy of BCMA-CAR T cells and prolonged remission.	Haematologica. 2023 Feb 1;108(2):568-580.
CD1 nude mice	Xenograft model	Oral gavage	8 mg/kg	Every 2 days for 20 days	Crenigacestat treatment significantly decreased the tumor volume and fibrotic reaction.	J Exp Clin Cancer Res. 2024 Oct 17;43(1):286.
Mice	PDX model and hydrodynamic model	Orally	8 mg/kg	Every two days for 3 weeks	Crenigacestat significantly reduced peritumoral liver fibrosis in both PDX and hydrodynamic models and inhibited the TGF-β1 pathway and CAF activation.	J Exp Clin Cancer Res. 2022 Nov 28;41(1):331.
CD-1 Nude mice	HuCCT1-xenograft model	Oral (gavage)	8 mg/kg	3 times/week for 4 weeks	Crenigacestat significantly inhibited NOTCH1 and HES1, but did not affect tumor growth. Additionally, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions.	Int J Mol Sci. 2022 Apr 10;23(8):4187
CD-1 Nude mice	iCCA xenograft model	Oral gavage	8 mg/kg	Every 2 days for 35 days	Crenigacestat significantly inhibited the growth of KKU-M213 and HuCCT1 xenograft tumors expressing high levels of CD90, indicating that Crenigacestat has therapeutic effects on CD90-positive tumors.	J Exp Clin Cancer Res. 2022 Feb 16;41(1):65

Species

NSG mice CD1 nude mice Mice CD-1 Nude mice CD-1 Nude mice

Animal Model

MM.1S xenograft model Xenograft model PDX model and hydrodynamic model HuCCT1-xenograft model iCCA xenograft model

Administration

Dosage

Frequency

Description

References

NSG mice

MM.1S xenograft model

Intraperitoneal injection

1 mg/kg

Once daily for 12 days

Combination treatment with ATRA and crenigacestat significantly enhanced the anti-myeloma efficacy of BCMA-CAR T cells and prolonged remission.

Haematologica. 2023 Feb 1;108(2):568-580.

CD1 nude mice

Xenograft model

Oral gavage

8 mg/kg

Every 2 days for 20 days

Crenigacestat treatment significantly decreased the tumor volume and fibrotic reaction.

J Exp Clin Cancer Res. 2024 Oct 17;43(1):286.

Mice

PDX model and hydrodynamic model

Orally

8 mg/kg

Every two days for 3 weeks

Crenigacestat significantly reduced peritumoral liver fibrosis in both PDX and hydrodynamic models and inhibited the TGF-β1 pathway and CAF activation.

J Exp Clin Cancer Res. 2022 Nov 28;41(1):331.

CD-1 Nude mice

HuCCT1-xenograft model

Oral (gavage)

8 mg/kg

3 times/week for 4 weeks

Crenigacestat significantly inhibited NOTCH1 and HES1, but did not affect tumor growth. Additionally, the drug triggered a strong immune response and blocked neovascularization in the tumor ecosystem of the HuCCT1-xenograft model without affecting the occurrence of fibrotic reactions.

Int J Mol Sci. 2022 Apr 10;23(8):4187

CD-1 Nude mice

iCCA xenograft model

Oral gavage

8 mg/kg

Every 2 days for 35 days

Crenigacestat significantly inhibited the growth of KKU-M213 and HuCCT1 xenograft tumors expressing high levels of CD90, indicating that Crenigacestat has therapeutic effects on CD90-positive tumors.

J Exp Clin Cancer Res. 2022 Feb 16;41(1):65

Crenigacestat 动物研究

Dose

Mice: 8 mg/kg^[3] (p.o.)

Administration

p.o.

Crenigacestat 参考文献

Crenigacestat 实验方案

计算器

存储液制备

1mg

5mg

10mg

1 mM

5 mM

10 mM

2.15mL

0.43mL

0.22mL

10.77mL

2.15mL

1.08mL

21.53mL

4.31mL

2.15mL

Crenigacestat 技术信息

CAS号	1421438-81-4
分子式	C₂₂H₂₃F₃N₄O₄
分子量	464.44
SMILES Code	O=C(N[C@@H](C)C(N[C@H]1C2=CC=CC=C2C3=CC=CN=C3N(CCO)C1=O)=O)CCC(F)(F)F
MDL No.	MFCD26142650

别名	LY3039478
运输	蓝冰
InChI Key	YCBAQKQAINQRFW-UGSOOPFHSA-N
Pubchem ID	71236992

存储条件

In solvent -20°C: 3-6个月 -80°C: 12个月

Pure form Sealed in dry, 2-8°C

溶解方案

细胞实验：

DMSO: 35 mg/mL(75.36 mM)，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO

动物实验：请根据您的动物给药指南选择适当的溶解方案。
以下溶解方案都请先按照体外实验的方式配制澄清的储备液，再依次添加助溶剂：
——为保证实验结果的可靠性，澄清的储备液可以根据储存条件，适当保存；体内实验的工作液，建议现用现配，当天使用；以下溶剂前显示的百分比是指该溶剂在终溶液中的体积占比；如在配制过程中出现沉淀、析出现象，可以通过加热和/或超声的方式助溶

方案一

方案二

方案三

细胞研究

细胞系	浓度	检测类型	检测时间	活性说明	数据源

A2780 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A2780 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00103 μM	24900678
A375 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human A375 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00048 μM	24900678
BxPC3 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human BxPC3 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00039 μM	24900678
CCRF-CEM cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human CCRF-CEM cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00076 μM	24900678
DLD1 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human DLD1 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00098 μM	24900678
HCT 116 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human HCT 116 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00072 μM	24900678
HEL 92.1.7 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human HEL 92.1.7 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00023 μM	24900678
Jurkat cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human Jurkat cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00595 μM	24900678
K562 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human K562 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00074 μM	24900678
MDA-MB-231	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MDA-MB-231 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.0005 μM	24900678
MIAPaCa2 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MIAPaCa2 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00071 μM	24900678
MOLT-3 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human MOLT-3 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00061 μM	24900678
SUP-T1 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human SUP-T1 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00124 μM	24900678
SW480 cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human SW480 cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.0001 μM	24900678
U-87-MG cells	Function assay	24 h	Inhibition of gamma-secretase mediated cleavage of Notch 1 in human U-87-MG cells assessed as nuclear accumulation of Notch 1 intracellular domain (N1ICD) after 24 hrs by ELISA, IC50=0.00028 μM	24900678

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全球学术期刊中引用的产品

Crenigacestat 质控信息

Crenigacestat 生物活性

Crenigacestat 细胞实验

Crenigacestat 动物实验

Crenigacestat 动物研究

Crenigacestat 参考文献

Crenigacestat 实验方案

Crenigacestat 技术信息

最近浏览的产品

大规格询价

摩尔计算器

靶点

总药量计算器

工作液计算器

细胞研究

临床研究

确认信息

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